Etoposide and cisplatin adjuvant chemotherapy

In patients who have high-volume metastases, the use of well-tolerated adjuvant chemotherapy should be strongly considered. Substitution of etoposide for vinblastine in two randomized studies of standard therapy for good- and poor-risk patients who had disseminated NSGCT showed less toxicity and equivalent or superior efficacy [7,29,30].

Based on the efficacy and tolerability of four cycles of EP in patients who had disseminated GCT, a prospective trial of two cycles of EP was conducted in the adjuvant setting [31]. Eligibility for the study was restricted to patients who had pN2 disease at RPLND, representing a group of patients who have an otherwise 50% or greater probability of relapse in surveillance. Fifty evaluable patients were treated in the study (Table 3) [31]. None of the 50 patients had relapsed at a median follow-up of 35 months (range 12-72 months) [31]. The stomatitis, dermatologic toxicity, and ileus reported with vinblastine-based adjuvant chemotherapy were not present in the etoposide-based chemotherapy [5,20,26,32]. No pulmonary or renal toxicity was noted, and neurotoxicity was minimal. The efficacy and tolerability of this regimen led the authors to regard two cycles of EP as the standard adjuvant regimen for patients who have pathologic stage N2 NSGCT.

A retrospective analysis was conducted of these 50 patients plus an additional 37 patients who were identified from a surgical database of patients undergoing RPLND who had been treated at MSKCC with two cycles of EP as adjuvant therapy for node-positive disease [33]. Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and 4 (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and 1 patient received an additional two cycles of EP following a transient marker increase after the first cycle. Eighty-seven patients are alive; 86 (98%) remain relapse-free at a median follow-up of 8 years (range 0.9-13.5 years) [33].

Table 3

Effective, low-toxicity adjuvant regimens in patients who have nonseminomatous germ cell tumors and high-volume metastases





Adjuvant etoposide and cisplatin (EP)a [33] Cisplatin

Adjuvant bleomycin, etoposide, and cisplatin (BEP) [35] Cisplatin ^

Adjuvant bleomycin, etoposide, and cisplatin (BEP) [35] Cisplatin ^

Bleomycin Weekly for 8 wks

30 IU

Bleomycin Weekly for 8 wks

30 IU

Abbreviation: RPLND, retroperitoneal lymph node dissection. a Relapse-free survival (8 yr) >98% (n = 87). b n = 86.

This analysis shows that two cycles of adjuvant etoposide plus cisplatin is effective adjuvant therapy for patients who have pathologic stage II disease. Of the 87 NSGCT patients in our series, 89% had pathologic stage N2 or higher. Treatment was well tolerated [10,33], and long-term toxicity was uncommon.

Past efforts to reduce chemotherapy-related toxicity in the management of advanced GCT also included replacement of vinblastine with etoposide, elimination or reduction of bleomycin, and reduction of treatment cycles. At our Center, we studied four cycles of cisplatin plus etoposide with elimination of bleomycin in patients who had good-risk metastatic GCT [34]. Our trial involving two cycles of etoposide plus cisplatin (EP) evolved as part of that effort (see Table 3).

In a retrospective series, two cycles of BEP have also been reported as an effective adjuvant regimen [35]. In a study of 86 patients, 49 (57%) had pathologic stage IIA disease on RPLND, whereas 37 (43%) had pathologic stage IIB disease on RPLND [35]. After RPLND, patients received two cycles of BEP (see Table 3). After a median follow-up of 85 months, 82 patients were evaluable, and 4 were lost to follow-up. Only 1 patient experienced relapse of a cervical node with teratoma; this patient is relapse-free after resection of disease. Toxicity was limited to 12% who suffered neutropenic fever during the course of therapy, although pulmonary function tests were not formally assessed [35].

Although two cycles of either EP or BEP may be considered for adjuvant therapy, we prefer EP because it avoids the use of bleomycin, and our data show more than 98% relapse-free survival with this regimen [33].

Primary management for patients who have clinical stage II disease often involves cisplatin combination chemotherapy before consideration of RPLND. Based on efficacy with the use of chemotherapy in the primary management of stage II NSGCT, patients who have clinical stage N2 or higher generally receive full-course chemotherapy before RPLND. In the rare instance in which pN3 disease is present at RPLND, our preference is full treatment with four cycles of EP or three cycles of BEP.

There is a higher risk for relapse in patients who have pN2 disease, and these patients are offered adjuvant chemotherapy after RPLND. Also, patients who have pN1 disease may choose adjuvant chemotherapy over observation. Adjuvant chemotherapy for noncompliant patients remains mandatory, however, and patients who have more advanced nodal disease (pN3) or unresected disease should receive full-course chemotherapy.

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